Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Abstract

Background and aims: Whether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histological severity of NASH.

Approach and results: Using the Duke NAFLD Clinical Database, we examined patients with biopsy-proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group-based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01).

Conclusions: Glycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH-related fibrosis progression.

FIG. 1

Flowchart of study population. Participants with alcohol consumption of ≥14 servings per week (for men) and at least ≥7 servings per week (for women) and those with alternative chronic liver disease other than NAFLD were excluded.

FIG. 2

Dose‐response relationship of mean HbA1c and the risk of severe hepatic histological outcome. ORs and 95% CIs (solid lines) plots derived from restricted cubic spline regression with three knots located at the 5th, 50th, and 90th percentiles are shown (reference HbA1c = 5.0%, 5th percentile). Age, sex, race, BMI, T2D, and hyperlipidemia were adjusted for in the model.

FIG. 3

Trajectory plots of HbA1c from 5 years preceding to 90 days following liver biopsy. Group 1: stable, good glycemic control (red); group 2: moderate glycemic control (green); and group 3: persistently poor glycemic control (blue). For each trajectory group, the solid line represents the predicted trajectory, and the dashed lines represent the 95% CIs.